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Background: The safety and oncological efficacy of laparoscopic re‐resection of incidental gallbladder cancer have not been studied. This study aimed to compare laparoscopic with open re‐resection of incidentally discovered gallbladder cancer while minimizing selection bias. Methods: This was a multicentre retrospective observational cohort study of patients with incidental gallbladder cancer who underwent re‐resection with curative intent at four centres between 2000 and 2017. Overall survival (OS) and recurrence‐free survival (RFS) were analysed by intention to treat. Inverse probability of surgery treatment weighting using propensity scoring was undertaken. Results: A total of 255 patients underwent re‐resection (190 open, 65 laparoscopic). Nineteen laparoscopic procedures were converted to open operation. Surgery before 2011 was the only factor associated with conversion. Duration of hospital stay was shorter after laparoscopic re‐resection (median 4 versus 6 days; P < 0·001). Three‐year OS rates for laparoscopic and open re‐resection were 87 and 62 per cent respectively (P = 0·502). Independent predictors of worse OS were residual cancer found at re‐resection (hazard ratio (HR) 1·91, 95 per cent c.i. 1·17 to 3·11), blood loss of at least 500 ml (HR 1·83, 1·23 to 2·74) and at least four positive nodes (HR 3·11, 1·46 to 6·65). In competing‐risks analysis, the RFS incidence was higher for laparoscopic re‐resection (P = 0·038), but OS did not differ between groups. Independent predictors of worse RFS were one to three positive nodes (HR 2·16, 1·29 to 3·60), at least four positive nodes (HR 4·39, 1·96 to 9·82) and residual cancer (HR 2·42, 1·46 to 4·00). Conclusion: Laparoscopic re‐resection for selected patients with incidental gallbladder cancer is oncologically non‐inferior to an open approach. Dissemination of advanced laparoscopic skills and timely referral of patients with incidental gallbladder cancer to specialized centres may allow more patients to benefit from this operation. [ABSTRACT FROM AUTHOR]

Background: The Delphi consensus study was carried out under the auspices of the International and Asia-Pacific Hepato-Pancreato-Biliary Associations (IHPBA-APHPBA) to develop practice guidelines for management of gallbladder cancer (GBC) globally., Method: GBC experts from 17 countries, spanning 6 continents, participated in a hybrid four-round Delphi consensus development process. The methodology involved email, online consultations, and in-person discussions. Sixty eight clinical questions (CQs) covering various domains related to GBC, were administered to the experts. A consensus recommendation was accepted only when endorsed by more than 75% of the participating experts., Results: Out of the sixty experts invited initially to participate in the consensus process 45 (75%) responded to the invitation. The consensus was achieved in 92.6% (63/68) of the CQs. Consensus covers epidemiological aspects of GBC, early, incidental and advanced GBC management, definitions for radical GBC resections, the extent of liver resection, lymph node dissection, and definitions of borderline resectable and locally advanced GBC., Conclusions: This is the first international Delphi consensus on GBC. These recommendations provide uniform terminology and practical clinical guidelines on the current management of GBC. Unresolved contentious issues like borderline resectable/locally advanced GBC need to be addressed by future clinical studies., (Copyright © 2024 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background: High-quality surgery plays a central role in the delivery of excellent oncologic care. Benchmark values indicate the best achievable results. We aimed to define benchmark values for gallbladder cancer (GBC) surgery across an international population., Patients and Methods: This study included consecutive patients with GBC who underwent curative-intent surgery during 2000-2021 at 13 centers, across seven countries and four continents. Patients operated on at high-volume centers without the need for vascular and/or bile duct reconstruction and without significant comorbidities were chosen as the benchmark group., Results: Of 906 patients who underwent curative-intent GBC surgery during the study period, 245 (27%) were included in the benchmark group. These were predominantly women (n = 174, 71%) and had a median age of 64 years (interquartile range 57-70 years). In the benchmark group, 50 patients (20%) experienced complications within 90 days after surgery, with 20 patients (8%) developing major complications (Clavien-Dindo grade ≥ IIIa). Median length of postoperative hospital stay was 6 days (interquartile range 4-8 days). Benchmark values included ≥ 4 lymph nodes retrieved, estimated intraoperative blood loss ≤ 350 mL, perioperative blood transfusion rate ≤ 13%, operative time ≤ 332 min, length of hospital stay ≤ 8 days, R1 margin rate ≤ 7%, complication rate ≤ 22%, and rate of grade ≥ IIIa complications ≤ 11%., Conclusions: Surgery for GBC remains associated with significant morbidity. The availability of benchmark values may facilitate comparisons in future analyses among GBC patients, GBC surgical approaches, and centers performing GBC surgery., (© 2023. Society of Surgical Oncology.)

Background: Gallbladder cancer (GBC) is rare but aggressive. The extent of surgical intervention for different GBC stages is non-uniform, ranging from cholecystectomy alone to extended resections including major hepatectomy, resection of adjacent organs and routine extrahepatic bile duct resection (EBDR). Robust evidence here is lacking, however, and survival benefit poorly defined. This study assesses factors associated with recurrence-free survival (RFS), overall survival (OS) and morbidity and mortality following GBC surgery in high income countries (HIC) and low and middle income countries (LMIC)., Methods: The multicentre, retrospective Operative Management of Gallbladder Cancer (OMEGA) cohort study included all patients who underwent GBC resection across 133 centres between 1st January 2010 and 31st December 2020. Regression analyses assessed factors associated with OS, RFS and morbidity., Findings: On multivariable analysis of all 3676 patients, wedge resection and segment IVb/V resection failed to improve RFS (HR 1.04 [0.84-1.29], p = 0.711 and HR 1.18 [0.95-1.46], p = 0.13 respectively) or OS (HR 0.96 [0.79-1.17], p = 0.67 and HR 1.48 [1.16-1.88], p = 0.49 respectively), while major hepatectomy was associated with worse RFS (HR 1.33 [1.02-1.74], p = 0.037) and OS (HR 1.26 [1.03-1.53], p = 0.022). Furthermore, EBDR (OR 2.86 [2.3-3.52], p < 0.0010), resection of additional organs (OR 2.22 [1.62-3.02], p < 0.0010) and major hepatectomy (OR 3.81 [2.55-5.73], p < 0.0010) were all associated with increased morbidity and mortality. Compared to LMIC, patients in HIC were associated with poorer RFS (HR 1.18 [1.02-1.37], p = 0.031) but not OS (HR 1.05 [0.91-1.22], p = 0.48). Adjuvant and neoadjuvant treatments were infrequently used., Interpretation: In this large, multicentre analysis of GBC surgical outcomes, liver resection was not conclusively associated with improved survival, and extended resections were associated with greater morbidity and mortality without oncological benefit. Aggressive upfront resections do not benefit higher stage GBC, and international collaborations are needed to develop evidence-based neoadjuvant and adjuvant treatment strategies to minimise surgical morbidity and prioritise prognostic benefit., Funding: Cambridge Hepatopancreatobiliary Department Research Fund., Competing Interests: SM has the following interests: 1) Principal investigator of a clinical trial on intrahepatic cholangiocarcinoma funded by BMS/Celgene (grant funding provided to institution, no personal compensation) 2) Advisory board member at Astra Zeneca on management of hepatocellular carcinoma and 3) Scientific Medical Advisory Board member Cholangiocarcinoma Foundation. None of the authors have any conflicts of interests to declare., (© 2023 The Author(s).)

Objective: Critical care air transport has played an important role during the coronavirus disease 2019 (COVID-19) pandemic. The goal of this article is to analyze results and lessons learned from the evacuation of the first 100 COVID-19 patients transported between medical facilities in Chile., Methods: We reviewed prospective data of patients who were referred for air transport between March 27, 2020, and July 9, 2020., Results: Of 115 referred patients, 100 were transported by air. All patients were intubated and mechanically ventilated. Hypertension, diabetes, and obesity were the most commonly observed comorbidities. Our service did not experience any major problems in patient care en route or among the crewmembers. We did not observe any severe acute respiratory syndrome coronavirus 2 infections among our flight team members during the study period. Twelve (12%) patients died at their destination intensive care unit, whereas the remaining 88 patients (88%) returned to their primary hospitals after recovery., Conclusions: Air transport of mechanically ventilated patients with COVID-19 infection has been shown to be a safe way of transport, with no in-flight deaths and an in-hospital mortality of 12%, which compares favorably with the in-hospital mortality of similar patients who did not undergo air transport., (Copyright © 2022. Published by Elsevier Inc.)

Background: Although gallbladder cancer (GBCA) is characterized by a dismal prognosis, there is a proportion of patients who are cured. The aim of this study was to analyze the profile of these patients., Methods: A database was queried for patients who underwent curative resection with a follow-up of at least 5 years. Patients were prospectively treated and registered by the same surgical team. A multivariate regression analysis was used to identify factors associated with long-term survival., Results: From 1988 to 2013, 461 patients were evaluated and 112 who underwent resection were analyzed. Among the patients, five year survival was 57% while lymph node and liver compromise were the only independent factors associated with survival. On the other hand, the elapsed time between the cholecystectomy and the resection, the differentiation grade and the level of wall invasion did not have an independent effect on the prognosis., Conclusion: Despite its poor prognosis, a subset of patients can be cured of GBCA. R0 resection of patients without lymph and liver infiltration are key to GBCA survival., (Copyright © 2020 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background: Data to guide surveillance following oncologic extended resection (OER) for gallbladder cancer (GBC) are lacking. Conditional recurrence-free survival (C-RFS) can inform surveillance. We aimed to estimate C-RFS and identify factors affecting conditional RFS after OER for GBC., Patients and Methods: Patients with ≥ T1b GBC who underwent curative-intent surgery in 2000-2018 at four countries were identified. Risk factors for recurrence and RFS were evaluated at initial resection in all patients and at 12 and 24 months after resection in patients remaining recurrence-free., Results: Of the 1071 patients who underwent OER, 484 met the inclusion criteria; 290 (60%) were recurrence-free at 12 months, and 199 (41%) were recurrence-free at 24 months. Median follow-up was 24.5 months for all patients and 47.21 months in survivors at analysis. Five-year RFS rates were 47% for the overall population, 71% for patients recurrence-free at 12 months, and 87% for the patients without recurrence at 24 months. In the entire cohort, the risk of recurrence peaked at 8 months. T3-T4 disease was independently associated with recurrence in all groups: entire cohort [hazard ratio (HR) 2.16, 95% confidence interval (CI) 1.49-3.13, P < 0.001], 12-month recurrence-free (HR 3.42, 95% CI 1.88-6.23, P < 0.001), and 24-month recurrence-free (HR 2.71, 95% CI 1.11-6.62, P = 0.029). Of the 125 patients without these risk factors, only 2 had recurrence after 36 months., Conclusion: C-RFS improves over time, and only T3-T4 disease remains a risk factor for recurrence at 24 months after OER for GBC. For all recurrence-free survivors after 36 months, the probability of recurrence is similar regardless of T category or disease stage.

Objective: To test the degree of agreement in selecting therapeutic options for patients suffering from colorectal liver metastasis (CRLM) among surgical experts around the globe., Summary/background: Only few areas in medicine have seen so many novel therapeutic options over the past decades as for liver tumors. Significant variations may therefore exist regarding the choices of treatment, even among experts, which may confuse both the medical community and patients., Methods: Ten cases of CRLM with different levels of complexity were presented to 43 expert liver surgeons from 23 countries and 4 continents. Experts were defined as experienced surgeons with academic contributions to the field of liver tumors. Experts provided information on their medical education and current practice in liver surgery and transplantation. Using an online platform, they chose their strategy in treating each case from defined multiple choices with added comments. Inter-rater agreement among experts and cases was calculated using free-marginal multirater kappa methodology. A similar, but adjusted survey was presented to 60 general surgeons from Asia, Europe, and North America to test their attitude in treating or referring complex patients to expert centers., Results: Thirty-eight (88%) experts completed the evaluation. Most of them are in leading positions (92%) with a median clinical experience of 25 years. Agreement on therapeutic strategies among them was none to minimal in more than half of the cases with kappa varying from 0.00 to 0.39. Many general surgeons may not refer the complex cases to expert centers, including in Europe, where they also engage in complex liver surgeries., Conclusions: Considerable inconsistencies of decision-making exist among expert surgeons when choosing a therapeutic strategy for CRLM. This might confuse both patients and referring physicians and indicate that an international high-level consensus statements and widely accepted guidelines are needed.

Background: Equipoise exists regarding the benefit of adjuvant therapy (AT) in patients with gallbladder cancer (GBC). The aim of this study was to critically review the available evidence for the effectiveness of AT in patients with GBC following surgery with curative intent., Methods: A systematic review was performed. Relevant studies were identified from Trip Database, BIREME-BVS, SciELO, Cochrane Central Register, WoS, MEDLINE, EMBASE and SCOPUS. Adjuvant therapies considered included chemotherapy, chemoradiotherapy, and radiotherapy. The primary outcome was overall survival (OS). Subgorup analysis of patients with positive lymph node disease (PLND), positive surgical margin (PSM), or advanced stage (AS) were performed., Results: 748 related articles were identified; 27 met the selection criteria (3 systematic reviews and 24 observational studies). Evidence provided was moderate, poor and very poor for chemotherapy, chemoradiotherapy, and radiotherapy. Existing evidence is not robust, but suggests certain benefits with AT in improving OS, especially in patients with PLND, PSM and AS., Conclusion: Results do not provide strong evidence that AT is effective in patients who undergo resection for GBC. Subgroups of PLND and PSM may have a survival advantage. Future studies with appropriate internal validity and adequate number of patients are required to better answer this question., (Copyright © 2019 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Competing Interests: Conflicts of Interest: The author has no conflicts of interest to declare.

Background: Residual disease (RD) has been described as one of the most relevant prognostic factors after radical surgical resection for incidental gallbladder cancer (IGC). The purpose of the present study was to analyze patterns of RD and determinant prognostic factors in patients undergoing re-resection for IGC., Methods: Patients undergoing re-exploration due to IGC between 1990 and 2014 were identified in two referral centers from different South-American countries. Patients submitted to a radical definitive operation were included in the study. Demographics and tumor-treated related variables were analyzed in correlation with RD and survival. The site of RD, local (gallbladder bed) or regional (lymph nodes and bile duct) was correlated with disease-specific survival (DSS)., Results: Of 265 patients with IGC submitted to surgery, 168 underwent a radical re-resection and RD was found in 58 (34.5%). Demographic, clinical and surgical variables were compared between both centers showing differences in type of resection, laparoscopic approach, T stages and disease stage. Location of RD was regional in 34 (20.2%) and local in 24 (14.3%), and no residual disease was found in 110 (65.5%) patients. T stage (T1b = 20%, T2 = 23.8%, T3 = 71.7%, p < 0.001) and disease stage (p < 0.001) were independent predictors of RD. Finding RD at any location reduced the DSS in comparison with non-RD patients (19.6 months vs. 62.7 months p < 0.001). No differences in DSS according to the location of RD were found, and all anatomic sites were equally poor (p = 0.27). RD at any site predicted DSS (p < 0.001), independently of all other IGC variables., Conclusions: IGC presented similar clinical parameters in two different countries of South America. RD was demonstrated as the most critical prognostic variable in patients with IGC treated by a radical resection. The presence of RD was associated with poor outcome, independently of any anatomic location. Future studies incorporating neoadjuvant chemotherapy in the treatment of patients with prognostic factors for RD are required to improve survival in this entity.

Gallbladder cancer (GBC) is a rare malignancy of biliary tract cancer (BTC), characterized by late presentation and poor prognosis. It exhibits wide geographical as well as ethnical variations. So, diverse epidemiology along with etiological factors have been discussed in the current article. Present review unravels the germ line polymorphisms contributing to GBC susceptibility through candidate gene approach and GWAS. GBC is enriched with multiple mutations consisting of both passenger and driver mutations. The identification of the hotspot driver mutations which are involved in the etiopathogenesis of this cancer is necessary, before targeted therapies could be implemented clinically. Thus, this review sheds lights on both traditional low throughput methods along with high throughput NGS used to determine somatic mutations in cancer. With the advent of GWAS and high throughput sequencing methods, it is possible to comprehend the mutational landscape of this enigmatic disease. This article is the first one to provide insights into the genetic heterogeneity of GBC along with somatic mutational data from Catalogue of Somatic Mutations in Cancer (COSMIC) database. In addition, management of tumor heterogeneity as a therapeutic challenge has been discussed. Future goals involve liquid biopsy based research for better clinical management of the disease. Therefore, research efforts involving discovery of non- invasive markers for early stage cancer detection along with novel therapies should be directed., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: The laparoscopic cholecystectomy has allowed the detection of an increasing number of incidental gallbladder cancers (IGBC). Although laparoscopy is employed in the management of a variety of abdominal tumors, its use in gallbladder cancer is reduced and controversial. This study analyzes the role of laparoscopy in gallbladder cancer with the focus in IGBC., Method: We evaluated our prospective series of 51 patients with an IGBC who were treated by laparoscopy between 2006 and 2016 at the Clinica Alemana in Santiago, Chile., Results: The series comprised 7 men and 44 women. Age ranged from 43 to 76 years (mean age 60). Regarding wall involvement, 29 patients had a T2 tumor, which was the most common. 8 and 14 patients had T1b and T3 tumors, respectively. Of the patients, 17 underwent only laparoscopic exploration. This was due to the presence tumor dissemination not being observed in the preoperative staging. 10 patients had to be converted to complete the resection, whereas 24 patients were laparoscopically resected. The quality of the resected material was not different between those who were converted and those who were treated by laparoscopy. In the laparoscopic group, the average number of harvested lymph nodes was 7.9, not statistically different from the converted group. The mean of hospital stay in the laparoscopic group (4.3 days) was significantly lower than the converted group., Conclusions: Laparoscopy has been shown to be a safe and feasible method for the management of IGBC. This method not only allows for a complete exploration, identifying a previously unseen residual tumor, but also makes it possible to accomplish the same oncology objectives as the open procedure. Therefore, laparoscopy should be considered a valid alternative in the management of IGBC.

Gallbladder cancer (GBC) is the second-leading cause of death from malignant tumors in Chilean women. The phosphatidylinositol 3-kinase (PI3K) pathway is involved in proliferation, cell survival, and growth. We investigated mutations in exons 9 and 20 of the PI3K gene in GBC. Mutations in exons 9 (E542K, E545G, E545K) and 20 (H1047L and H1047R) of PI3K were determined by direct sequencing in 130 cases of GBC. The patient group consisted of 110 women and 20 men, and mutations were found in 22 cases (16.9%). Of these, 14 cases had mutations in exon 9 (63.6%) (E542K, 64%; E545K, 29%; and E545G, 7%) and 8 in exon 20 (37.4%; H1047L, 50%; H1047R, 50%). No differences were noted in the frequency and type of mutations analyzed by sex, age, or histologic features. We observed mutations in 22% of the early-stage GBC and 14.6% of the advanced cases. In this series of GBC, 17% of cases were noted as having mutations in either exons 9 or 20 of PI3K. These results suggest that therapeutic testing of inhibitors of the PI3K/AKT pathway may be of benefit in advanced GBC patients., (Copyright © 2016 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.)

Background: PTEN is a tumor suppressor gene that regulates the PTEN/PI3k/AKT/mTOR pathway, which is frequently altered in human cancers including gallbladder cancer (GBC). To determine the frequency of PTEN expression in GBC and to establish its relation to clinical and morphological parameters and survival in GBC., Methods: The immunohistochemical expression of PTEN was studied in 108 GBC. All the cases included areas of non-tumor mucosa adjacent to the tumor., Results: The group was comprised of 108 patients, 91 women (84.3%) and 17 men (15.7%) with an average age of 65.2 years (SD ± 12.3 years). Thirty-five cases (33%) were early carcinomas (EC) and the remaining 73 (67%) were advanced cases (AC). All the internal controls were positive (moderate or intense in 96.3%). Only in three AC (4.1%) was there a complete absence of PTEN immunohistochemical expression. There were no significant differences in relation between PTEN expression and tumor infiltration or degree of differentiation. The three patients with PTEN inactivation died before 10 months; however, the other patients with AC had a survival of 53% at 10 months., Discussion: Loss of PTEN expression was observed in 4.1% of the advanced GBC. All the patients with this alteration died before 10 months. PTEN inactivation could be a rare event, but with a poor prognosis in advanced GBC.

Purpose of Review: Gallbladder cancer (GBC) should be considered an orphan disease in oncology and represent a unique carcinogenetic model. This review will analyse some of the current aspects of GBC., Recent Findings: Chile has the highest incidence and mortality of GBC in the world. Most patients are diagnosed in advanced stages with few treatment options. During the last two decades, little progress has been made in early diagnosis and treatment. At the molecular level, recent access to next-generation sequencing and other techniques for detecting the mutations of multiple genes have made advances in this area., Summary: The use of therapies targeted according to the detection of specific molecular alterations is in the early stages of evaluation and could represent a significant advance in the treatment of a large number of patients from developing countries.

Objective: To determine the prognostic impact of tumor location in gallbladder cancer., Background: Depth of tumor is a strong predictor of survival after curative resection of gallbladder cancer. However, the gallbladder has a unique anatomical relationship with the liver, and the clinical significance of tumor location remains unclear., Methods: For 437 patients with gallbladder cancer who underwent resection at 4 international institutions, clinicopathologic characteristics and their association with survival were analyzed. Tumor location was defined as "hepatic side" or "peritoneal side," and the prognostic significance of tumor location was evaluated., Results: Among the 252 patients with T2 disease, patients with tumors on the hepatic side (T2h, n = 99) had higher rates of vascular invasion, neural invasion, and nodal metastasis than patients with tumors on the peritoneal side (T2p, n = 153) (51% vs 19%, 33% vs 8%, and 40% vs 17%, respectively; P < 0.01 for all). After a median follow-up of 58.9 months, 3-year and 5-year survival rates were 52.1% and 42.6%, respectively, for T2h tumors and 73.7% and 64.7%, respectively, for T2p tumors (P = 0.0006). No such differences were observed in T1 or T3 tumors. Multivariate analysis confirmed the independent association of hepatic-side location with survival in T2 tumors (hazard ratio, 2.7; 95% confidence interval, 1.7-4.2; P < 0.001). This subclassification of T2 tumors predicted recurrence in the liver (23% vs 3%; P = 0.003) and distant lymph nodes (16% vs 3%; P = 0.019) even after radical resection., Conclusions: After curative resection of T2 gallbladder cancer, tumor location predicts the pattern of recurrence and survival.

Objectives: To explore gallbladder cancer (GBC), the second leading cause of cancer-related death in women in Chile., Methods: Analysis of macroscopic and microscopic variables, morphometry, and survival in 1,366 patients with GBC., Results: Patients comprised 1,138 women and 228 men; diagnoses included 213 (15.6%) cases of mucosal carcinoma, 132 (9.7%) cases of muscular carcinoma, 316 (23.1%) cases of subserosal carcinoma, 382 (28.0%) cases of serosal carcinoma, and 323 (23.6%) cases beyond the serosa. Women older than 55 years with a gallbladder length greater than 9.5 cm had a five-times-greater relative risk of cancer. Those with a gallbladder wall thickness less than 7 mm had a better 5-year survival rate than those with a gallbladder wall thickness greater than 10 mm (P = .0001). Patients who had cholesterolosis of the gallbladder had 9.2 times less probability of having cancer. The infiltration level of the gallbladder wall was the most important independent prognostic factor (P < .001), followed by differentiation and lymphatic involvement (P < .001 and P = .05, respectively). Vascular infiltration had a mortality rate of 100%., Conclusions: Morphologic features are strongly associated with the prognosis of GBC and must be taken into consideration when supplementary treatment is recommended.

Background: The HER2/neu gene is a proto-oncogene that can predict the response to treatment with trastuzumab, pertuzumab, and lapatinib. This study was conducted to determine the frequency of HER2/neu overexpression and to identify a subgroup of patients with gallbladder cancer who would benefit from targeted therapy., Methods: Patients with gallbladder cancer (n = 187; 165 women and 22 men) with a recorded follow-up of at least 5 years were included, along with control subjects (n = 75). An automated immunohistochemical technique was used with an anti-ErbB2 antibody. Scoring was conducted according to the CAP/ASCO (College of American Pathologists/American Society of Clinical Oncology) criteria for breast cancer., Results: Overexpression of HER2/neu was observed in 12.8% of the cases. Of those, 0% were mucosal, 14.3% muscular, 12.8% subserosal, and 10.6% serosal. In 20% of the cases, equivocal staining was observed. Overexpression was more frequent in the advanced cancers and in the better differentiated tumors (13.8% and 17.4%, respectively), but the difference was nonsignificant. The patients with overexpression of HER2/neu had a worse overall survival, when compared with those who had no expression at 5 years (34% vs. 41%)., Conclusion: This is the single largest study of HER2/neu expression in gallbladder cancer to use commonly accepted scoring criteria. The results indicate that HER2/neu overexpression occurred in 14% of the advanced gallbladder cancer cases. This subgroup may benefit from inhibitors of the HER2/neu pathway.

Gallbladder cancer is now considered a distinct clinical entity, allowing for a separate analysis from that of other malignancies of the biliary tree. Symptoms related to a malignant tumor of the gallbladder include jaundice and abdominal pain, or a palpable abdominal mass that occurs in a late stage of the disease. The majority of patients with operable gallbladder cancer are diagnosed by cholecystectomy performed for presumed benign disease, mostly cholelithiasis, a clinical entity known as incidental gallbladder cancer. Given the poor prognosis if tumor invasion beyond the muscular layer and/or nodal metastasis is found, adjuvant treatments have been implemented, but few data are available to guide treatment decisions in this setting. For advanced disease, a multidisciplinary treatment approach including biliary drainage procedures and palliative support is needed in the management of this aggressive disease. Palliative chemotherapy with a combination of gemcitabine and cisplatin or oxaliplatin is the standard treatment based on the findings of two phase III trials that showed improved overall survival compared to single-agent chemotherapy and best supportive care. Several phase II studies have been reported investigating the role of targeted agents against EGFR, VEGF, HER2, and MEK. International collaboration to enhance our knowledge of gallbladder cancer should be encouraged.

Background: Bariatric surgery is increasingly being performed and sleeve gastrectomy (SG) has proved to be effective and safe. Among its complications, leaks are the most serious and life threatening., Methods: The focus of the study is nine patients who underwent a SG and developed a gastric leak after surgery. Our data were obtained from the clinical charts of the patients and through interviews with the surgeon who performed the index surgery., Results: Eight patients underwent SG at outside institutions while one was operated at Clinica Alemana. Three patients developed symptoms within 5 days after surgery, while the rest were diagnosed after 10 days from the surgery. A CT scan was the method used to confirm the diagnosis in all patients. The three patients who had a leak detected during the immediate postoperative period underwent laparoscopic reoperation. Among the rest of the patients, percutaneous drainage was employed in one patient as the primary procedure while the other underwent surgical drainage. An esophageal endoluminal stent was employed in four patients. The leak closed in all patients with the healing time ranging from 21 to 240 days., Conclusions: Diagnosis of a leak after a SG required a greater index of suspicion in order to perform an early diagnosis. Sepsis control and nutritional support are the cornerstones of this treatment. Evolution is characterized by longer periods of time that are necessary in order to wait until the leak closes. Management must be tailored to each patient.

Gallbladder cancer (GBC) is the main cause of death by malignant tumour in women in Chile. There is no information regarding the role of excision repair cross-complementing group 1 (ERCC1) in GBC. Our aim is to determine the expression and significance of ERCC1 as a prognostic factor in GBC. Tissue microarrays were prepared using 200 surgically resected GBCs and 50 non-malignant gallbladders as controls. In 190 cases, ERCC1 was determined by immunohistochemistry. The correlation between ERCC1 expression and GBC pathological characteristics and patient survival were analysed. Ninety-five percent of the non-malignant gallbladder epithelia showed intense and diffuse ERCC1 expression. GBC cases showed ERCC1 expression in the tumour cells in 100/190 (53%) cases. The best differentiated tumours showed significantly greater expression than the less differentiated (p<0.05). Patients with ERCC1-positive status with subserosal carcinomas (pT2) had significantly better survival than ERCC1-negative patients at 20 and 60 months of follow-up (p=0.005), and the probability of dying was 6 times lower for ERCC1-positive than for ERCC1-negative patients. Our preliminary results show that chole-cystectomised patients with GBC in stage pT2 and with ERCC1 expression have significantly better survival than patients at the same stage that did not present ERCC1 expression.

Background: The aim of this study was to evaluate the role that laparoscopy plays in the management of gallbladder cancer., Method: From August 2005 to March 2009, 23 patients affected by gallbladder cancer detected after the study of a cholecystectomy specimen underwent laparoscopy as part of their management., Results: Among the patients, 5 underwent only an exploratory laparoscopy, while 11 were converted due to the existence of dense adhesions that precluded a complete exploration. Of the patients with adhesions who underwent conversion, three were unresectable. The remainder underwent a lymphadenectomy and liver resection after conversion. Of the seven who underwent a complete laparoscopic exploration, five had a lymphadenectomy and liver resection done completely by laparoscopy while conversion was needed for two. Conversion was required due to lymphatic metastasis at the hepatic pedicle and the presence of a bile leak. Postoperative time was uneventful, with patients discharged within 3 days of the operation., Conclusions: Laparoscopy may be employed in the management of patients with early forms of gallbladder cancer undergoing reoperation. Although the presence of adhesions may result in inadequate exploration, there is a subset of patients for whom it is possible to perform a complete exam. Furthermore, laparoscopic lymphadenectomy and gallbladder bed resection is a promising technique in well-selected patients.

Background: The different bariatric surgery techniques that alter the digestive anatomy also modify the gastric absorption surface. Since alcohol is a substance that is mainly metabolized in the stomach, the goal of this study was to determine alcohol absorption before and after a laparoscopic sleeve gastrectomy (LSG) in the same patients., Methods: Studies were carried out on 12 morbidly obese patients who underwent a LSG (eight men and four women). Each patient was given 3.6 ml of red wine to drink at 14% for each liter of body water mass. Alcotest values (Alcoscan Alcomate AL-6000) were measured 10 min after the wine dose had been consumed. Measurements were then repeated every 5 min until the alcohol had been completely eliminated from the bloodstream. During the postoperatory period (median of 2.3 months), the measurement was repeated with the total dose per kg adjusted to the new water body mass. The results were measured with a nonparametric analysis for repeated samples., Results: The maximum average peak of the Alcotest was 2.02 g/l during the postoperative period compared to 0.87 g/l during the preoperative period (p = 0.001 Wilcoxon). At 175 min, the blood alcohol level value reaches zero (0) in all pre-operatory patients, while after surgery, an average value of 0.26 g/l was observed (p = 0.027 Wilcoxon). After 4 h, an Alcotest average of 0.20 g/l was observed in these patients., Conclusion: Alcohol absorption was considerably modified after LSG with higher and longer blood alcohol values for equivalent amounts of alcohol.

Background and Objectives: The goal of this study was to evaluate a series of patients with early gallbladder cancer, focusing on the selection of treatment and the role of Rokitansky Aschoff sinus infiltration., Methods: We performed a retrospective analysis of a prospective series of 371 patients with gallbladder cancer. Specimens were reviewed by an independent pathologist to confirm the diagnosis and depth of infiltration and to evaluate the presence of Rokitansky Aschoff sinus involvement., Results: Forty-nine and 45 patients with muscular (pT1b) and mucosal (pT1a) infiltration gallbladder cancer tumors were studied respectively. Simple cholecystectomy was the treatment in all patients, with the exception of 11 patients who underwent further surgery. Rokitansky Aschoff sinus invasion was seen in seven patients with mucosa (pT1a) and three with muscular (pT1b) compromise. The 5-year survival rates of patients with muscular (pT1b) and mucosal (pT1a) infiltration were 87.6% and 86.4%, respectively. Patients with Rokitansky Aschoff involvement had a lower survival rate than those with no involvement in both categories., Conclusions: Early gallbladder cancer is associated with a favorable prognosis and cholecystectomy should be the standard treatment. Despite some patients having a worse prognosis, there are no data to support more aggressive treatment.

Gallbladder cancer (GC) is considered a rare disease associated with a poor prognosis. Unfortunately, the low number of cases makes the performance of trials addressing the role of adjuvant, neoadjuvant, and/or palliative therapy difficult. For a long time, the majority of trials were 5-fluorouracil (5 FU)-based, and results were uniformly poor. Since the introduction of Gemcitabine, response rates of approximately 30% have been observed through the use of this drug and new approaches have been tested. In this sense, drugs such as Cisplatin and Capecitabine have been employed concurrently with gemcitabine and/or radiation. Since a recurrence pattern is both distant and local, chernoradiation seems a logical option to deal with the disease. However, at the present time, the lack of valid and scientific evidence means that most of the recommendations originate from trials dealing with other tumors, such as pancreas cancer and biliary tract cancer (BTC). The aforementioned treatment alternatives warrant further evaluation focusing on GC., (Copyright 2006 Wiley-Liss, Inc.)

Background: Gallstones are considered the most important risk factor for gallbladder cancer., Aim: To identify differences in the number, weight, volume, and density of gallstones associated with chronic cholecystitis (CC), gallbladder dysplasia (GD), and gallbladder cancer (GBC)., Methods: A total of 125 cases were selected, of which 93 had gallstones associated with GBC and 31 had gallstones associated with GD. The controls were those with CC, matched by sex and age. The number, weight, volume, and density of these gallstones were examined in order to determine differences and relative cancer risk., Results: Number: Multiple gallstones were present in over 76% of cases (GBC and GD) and controls (P = ns). The average number of multiple stones was 21 in GBC versus 14 in controls (P < 0.01). Weight: The average weight of the gallstones was 9.6 g in GBC versus 6.0 g in controls (P = 0.0004). The average weight in multiple stones over 10 g had strong association with GBC (P = 0.0006). Volume: The average volume was 11.7 and 6.48 ml in GBC and controls (P = 0.0002). Average volumes of 6, 8, and 10 ml had a relative cancer risk of 5, 7, and 11 times, respectively. Size: No differences were shown between GBC, GD, and controls., Conclusions: The volume of gallstones associated with other risk factors of GBC may be helpful in prioritizing cholecystectomies in symptomatic patients., (Copyright 2006 Wiley-Liss, Inc.)

Background: Gallbladder cancer is an uncommon disease except in countries like Chile and areas of India and Japan. The knowledge regarding the etiology and mechanisms through which this neoplasia is developed is significantly less compared to other malignant tumors., Results: The epithelial lesions involved in gallbladder carcinogenesis are dysplasia and adenomas that represent two biologically distinct carcinogenetic models. Dysplasia progresses to carcinoma in situ (CIS) and subsequently becomes invasive. Over 80% of invasive gallbladder cancers present areas adjacent to the CIS and epithelial dysplasia. Other authors have demonstrated adenomatous areas in carcinomas, or malignant transformation in an adenoma. The low incidence of gallbladder adenomas (0.14% of cholecystectomies) and the presence of adenomatous remnants in the neighboring mucosa to early carcinomas in less than 3% of the cases suggest the limited importance of this carcinogenic pathway. Epithelial dysplasia which is not associated with gallbladder cancer is observed in approximately 1% of cholecystectomies for symptomatic lithiasis. Metaplasia, dysplasia, and CIS are present in the mucosa adjacent to the cancer in 66%, 81.3%, and 69%, respectively. The average ages of patients with dysplasia not associated to cancer (51.9 years), early carcinomas (56.8 years), and advanced carcinomas (62.9 years) demonstrate a gradient which suggests the progression of these lesions., Conclusions: From the morphological point of view, the dysplasia-carcinoma sequence is the most plausible carcinogenic pathway for gallbladder cancer, a process which would require a period of approximately 10 years., (Copyright 2006 Wiley-Liss, Inc.)

Background: Methylation in the promoter region of genes is an important mechanism of inactivation of tumor suppressor genes. Our objective was to analyze the methylation pattern of some of the genes involved in carcinogenesis of the gallbladder, examining the immunohistochemical expression of proteins, clinical features, and patient survival time., Methods: Twenty cases of gallbladder cancer were selected from the frozen tumor bank. The DNA extracted was analyzed by means of a methylation-specific polymerase chain reaction test for the CDKN2A (p16), MLH1, APC, FHIT, and CDH1 (E-cadherin) genes. Morphological and clinical data and follow-up information were obtained., Results: All cases were in an advanced stage: histologically moderate or poorly differentiated tumors (95%). Methylation of the promoter area of genes was observed in 5%, 20%, 30%, 40%, and 65% of cases, and an altered immunohistochemical pattern (AIP) in 5%, 35%, 21%, 25%, and 66% for the MLH1, CDKN2A, FHIT, APC, and CDH1 genes, respectively. The Kappa concordance index between methylation of the promoter area and AIP for the MLH1 and CDH1 genes was very high (K > 0.75) and substantial for APC (K > 0.45). No correlation was found between survival time and the methylation of the genes studied., Conclusions: The high frequency of gene methylation (with the exception of MLH1) and the high agreement between AIP and methylation of the gene promoter area for the MLH1, APC, and CDH1 genes suggest that the inactivation of tumor suppressor genes and of the genes related to the control of cellular proliferation through this mechanism is involved in gallbladder carcinogenesis.

The goal was to study our experience in the management of a series of patients with a potentially curative subserosal gallbladder cancer who were prospectively treated by the authors. Between April 1988 and July 2004, 139 patients were enrolled in our prospective database. Of the above, 120 were operated on with an open procedure and the rest with laparoscopic surgery. In only eight patients was the diagnosis suspected before the cholecystectomy. The majority of tumors were adenocarcinoma. Six patients had an epidermoid tumor, and one had a carcinosarcoma. Of the patients, 74 underwent reoperation, while in 55 (70.2%) it was possible to perform an extended cholecystectomy with a curative aim. Operative mortality was 0%, and operative morbidity was 16%. Lymph node metastases were found in 10 (18.8%), while in 7 (13.2%) the liver was involved. The overall survival rate was 67.7%, while in those who underwent resection, the survival rate was 77%. Through the use of a multivariate analysis, the presence of lymph node metastasis was found to be an independent factor with respect to prognosis. The feasibility of performing an extended cholecystectomy in patients with gallbladder cancer and invasion of the subserosal layer allows for a good survival rate. The presence of lymph node metastases represents the main poor prognosis factor, and some type of adjuvant therapy should be studied in this particular group.

Background/aims: Although the most frequent cause of death after curative resection of advanced gastric cancer is peritoneal recurrence, there was no effective therapy for the prevention of peritoneal recurrence. This randomized trial sought to determine whether intraoperative chemohyperthermic peritoneal perfusion could eliminate microscopic residual disease and thereby improve survival of patients with advanced gastric cancer., Methodology: One-hundred and thirty-nine patients with T2-4 gastric cancer underwent curative gastrectomy with extended lymphadenectomy. These patients were randomly allocated into the following three groups. Patients in the CHPP group received surgery + chemohyperthermic peritoneal perfusion, and those in the CNPP group underwent surgery + chemonormothermic peritoneal perfusion. The third group was surgery alone group. In the CHPP and CNPP groups, peritoneal cavity was perfused with 6-8 liters of heated saline at, respectively, 42-43 degrees C and 37 degrees C with 30 mg of mitomycin C and 300 mg of cisplatin by a extracorporeal circulation machine., Results: Major operative complication occurred in 19% (9/48), 14% (6/44) and 19% (9/47) of the CHPP, CNPP and surgery alone group, respectively. Complication which uniquely developed after chemohyperthermic peritoneal perfusion was bowel perforation. Mortality rates of each group were 4% (2/48), 0% (0/44) and 4% (2/47) in the CHPP, CNPP and surgery alone group, respectively. Overall 5-year survival rates of CHPP, CNPP and surgery alone groups were 61%, 43% and 42%, respectively. In a subset analysis, patients with gastric cancer having serosal invasion or lymph node metastasis have shown a statistically significant improvement in survival when treated with chemohyperthermic peritoneal perfusion. However, chemonormothermic peritoneal perfusion had no survival benefit. By analyzing with Cox proportional hazard model, chemohyperthermic peritoneal perfusion emerged as an independent prognostic factor for good survival. Surgery alone had three-fold higher risk of death than chemohyperthermic peritoneal perfusion., Conclusions: Chemohyperthermic peritoneal perfusion had an efficiency for the prophylaxis of recurrence after curative resection of advanced gastric cancer, and is indicated for patients with tumor infiltrating beyond serosal layer and node positive tumor.

In spite of the fatal course associated with patients with gallbladder cancer, there is a subgroup of them in whom prognosis could be improved. Although early gallbladder cancer is considered a tumor with invasion of the mucosa or the muscular layer, in this manuscript we analyze those with invasion confined to the gallbladder. Pre-operative diagnosis of these patients is rare with cholecystectomy specimen histologic analysis being the most common way of detecting these tumors. The level of wall invasion represents a useful and practical way of dividing the patients according to their prognosis and treatment. Mucosal and muscular invasion tumors could be cured by simple cholecystectomy. Among patients with a tumor confined to the gallbladder, those with subserosal infiltration represent the largest group. Residual tumor after cholecystectomy is a common fact in these patients, thus a more aggressive procedure than simple cholecystectomy should be performed. Generally, extended cholecystectomy is the preferred approach for dealing with these patients. Unfortunately, in spite of the employment of extended and potentially curative surgery, prognosis is still poor and additional therapeutic procedures are needed. Finally, when tumors compromise the serosal layer, 5-year survival is poor irrespective of the type of therapy. However, well-selected cases deserve to undergo aggressive treatment.